Method for treating diabetes obesity and conditions characterized by increased protein breakdown with novel oxazolidines

ABSTRACT

The oxazolidines of the formula ##STR1## wherein n signifies the number 1 or 2. 
     T signifies lower carbalkoxy. 
     X signifies phenoxymethyl optionally mono-fluorinated or mono-chlorinated in the ortho-position or phenyl optionally monosubstituted by fluorine, chlorine, trifluoromethyl or lower-alkoxy. 
     Y signifies hydrogen or methyl, and 
     Z signifies a phenyl or thienyl residue substituted in a defined manner. 
     and the physiologically compatible salts thereof have catabolic activity and can be used for the treatment of obesity and diabetes mellitus or for the treatment of conditions which are associated with an increased protein breakdown, or as feed additives for fattening animals. They are manufactured starting from corresponding primary amines.

This is a division of application Ser. No. 667,186 filed Nov. 1, 1984,now U.S. Pat. No. 4,743,604.

The present invention is concerned with novel oxazolidines, a processfor their manufacture and pharmaceutical preparations based on thesecompounds.

The oxazolidines in accordance with the invention are compounds of theformula ##STR2## wherein n is the number 1 or 2,

T is lower-carbalkoxy,

X is phenoxymethyl optionally mono-fluorinated or mono-chlorinated inthe ortho-position or phenyl optionally monosubstituted by fluorine,chlorine, trifluoromethyl or lower-alkoxy,

Y is hydrogen or methyl,

Z is a group of the formula ##STR3## R¹ is lower-alkyl, optionallyN-mono-lower-alkylated or N-di-lower-alkylated aminomethyl or a residue--C(O)R², --C(R³)═CH--(CH₂)_(m) --C(O)R², --C(H,R³)--(CH₂)_(m+1)--C(O)R², --C(H,R³)--(CH₂)_(p) --OH or --C(R³)═CH--C(CH₃)═CH--COOCH₃,

R¹¹ is hydroxy, lower-alkoxy, lower-alkanoyloxy, sulphamoyl, benzyloxyor phenoxy optionally ring-substituted by fluorine, chlorine,trifluoromethyl, lower-alkyl or lower-alkoxy, or a group R¹, ##STR4## R²is hydroxy, lower-alkyl, lower-alkoxy, dimethylaminoethoxy,lower-alkoxycarbonylethyl or optionally mono-lower-alkylated ordi-lower-alkylated amino.

R³ is hydrogen or methyl,

R⁴ is lower-alkyl,

R⁵ is hydrogen, lower-alkyl or phenyl optionally para-substituted bychlorine, fluorine, trifluoromethyl, lower-alkyl or lower-alkoxy,

R⁶ is lower-alkyl or phenyl optionally para-substituted by fluorine,chlorine, lower-alkyl or lower-alkoxy,

m and p are whole numbers of 0 to 6,

v is a whole number of 2 to 4,

q and t are whole numbers of 1 to 6, and physiologically compatiblesalts thereof.

The term "lower" used herein denotes residues with 1-6 carbon atoms,residues with 1-4 carbon atoms being preferred. Alkyl and alkoxy groupscan be straight-chain or branched. Examples are methyl, ethyl, propyl,isopropyl, n-butyl and isobutyl and methoxy, ethoxy, propoxy,isopro-poxy, butoxy and isobutoxy, respectively. Lower-alkanoyloxyresidues are derived from lower-alkanecarboxylic acids such as formicacid, acetic acid, propionic acid and butyric acid.

The compounds of formula I form acid addition salts with acids, whichare likewise an object of the invention. Examples of such salts aresalts with physiologically compatible mineral acids such as hydrochloricacid. hydrobromic acid, sulphuric acid, phosphoric acid; or with organicacids such as methanesulphonic acid, acetic acid, propionic acid, citricacid, oxalic acid, succinic acid, malic acid, fumaric acid, phenylaceticacid or salicylic acid. Carboxylic acids of formula I can exist assalts. Examples of such salts are alkali metal, alkaline earth metal,ammonium and alkylammonium salts such as Na, K, Ca, trimethylammoniumand ethanolammonium salts.

The compounds of formula I contain at least two asymmetric carbon atomsand can therefore exist as optically active enantiomers, asdiastereomers or as racemates.

The compounds of formula I can be obtained in accordance with theinvention by reacting an amine of the formula ##STR5## wherein n, X, Yand Z have the significance given above, with a compound of the formulaTCHO, wherein T is lower-carbalkoxy, and, if desired, converting acompound of formula I obtained into a salt.

The reaction of an amine of formula II with a compound of the formulaTCHO is conveniently carried out in a solvent, preferably an aromatichydrocarbon such as benzene or toluene, and at room temperature or atelevated temperature, preferably by azeotropic distillation of thereaction mixture.

The compounds of formula II can be obtained by

(a) reacting an epoxide of the formula ##STR6## or a β-keto halide ofthe formula ##STR7## with an amine of the formula ##STR8## and reducinga --C(O)-- group present in a compound obtained to a --CHOH-- group, or

(b) reducing a compound of one of the formulae ##STR9##

(c) if desired, functionally modifying reactive substituents present ina group Z of a compound of formula II.

The reaction of a compound of formula II-1 or III-1 with a compound offormula IV can be carried out in an inert organic solvent, convenientlya protic solvent such as a lower alkanol, e.g. ethanol. The reactiontemperature is not critical, it can lie between room temperature and thereflux temperature of the reaction mixture.

The reduction of a compound of formula V can be carried out by catalytichydrogenation, e.g. in the presence of noble metal catalysts such as Pdor Pt catalysts, or by treatment with a complex metal hydride such asNaBH₄. The reaction conditions which are usually used for suchreductions can be used in this case. The catalytic hydrogenation isconveniently carried out in an inert organic solvent such as a loweralkanol, e.g. ethanol, at room temperature or a slightly elevatedtemperature, e.g. at 20°-80° C. The reduction with a complex metalhydride is conveniently carried out in a lower alkanol, e.g. methanol,at temperatures of 20°-30° C.

The compounds of formulae VI to IX can be reduced with a complex metalhydride in analogy to the compounds of formula V. NaBH₄ is a suitablecomplex metal hydride for the reduction of the compounds VI and VII. Thecompounds VIII are conveniently reduced with LiAlH₄.

A keto group X--C(O)-- which results in the reaction of a compound III-2with a compound IV can be reduced in a manner known per se to thesecondary alcohol group. This reduction can be carried out under thesame conditions as for the reduction of the compounds V-IX describedabove, whereby the reduction with a complex metal hydride, especiallyNaBH₄, is preferred because of its selectivity.

A reactive substituent, especially a group --C(O)R² or--C(R³)═CH--(CH₂)_(m) --C(O)R², in the thus-obtained reaction product offormula II can be functionally modified. The esterification of acarboxyl group can be carried out in a manner known per se, e.g. bymeans of alkyl halides such as methyl iodide and a base. Thesaponification of an ester group is conveniently carried out underalkaline conditions, e.g. by means of aqueous-alcoholic alkalihydroxide, e.g. aqueous-methanolic potassium hydroxide. A double bondpresent in a side-chain R¹ or R¹¹ can be hydrogenated to a single bonde.g. in the presence of a catalyst such as palladium-on-carbon in asolvent such as a lower alkanol, e.g. ethanol. A hydroxy residue R¹¹ canbe etherified in a manner known per se, e.g. by reaction with a mesylateor halide corresponding to the ether residue and in the presence of abase such as potassium hydroxide in a solvent such as a lower alkanol,e.g. n-propanol, or in the presence of potassium t-butylate in a solventsuch as DMSO.

An optionally mono-lower alkylated or di-lower alkylated carbamoyl groupR¹ or R¹¹ can be reduced to the corresponding aminomethyl group byreduction e.g. with complex metal hydrides such as LiAlH₄. Alower-alkoxycarbonyl group can be reduced to the hydroxymethyl group inan analogous manner.

The compounds of formulae V--IX can be prepared in a manner known perse, e.g. the compounds of formula VIII can be prepared by reacting anacid of the formula X¹ --C(H,OH)--COOH with an amine of formula IV.

Preferred compounds of formula I are those in which the substituent R¹¹present on a phenyl group Z is hydroxy, lower alkoxy, lower-alkanoyloxy,sulphamoyl or a group R¹, --O--(CH₂)_(q) --OH, --O--(CH₂)_(q) --COOR⁴,--O--(CH₂)_(q) --O--(CH₂)_(t) --R⁵ and R⁵ is hydrogen, lower-alkyl orphenyl.

Preferred compounds of formula I are, further, those in which T iscarbomethoxy.

Preferred compounds of formula I are, further, those in which X isphenyl monosubstituted by chlorine or trifluoromethyl in themeta-position, or phenoxymethyl, especially those in which the C-atombonded to a phenoxymethyl residue X has the S-configuration or theC-atom bonded to a phenyl residue X has the R-configuration.

Furthermore, there are preferred those compounds of formula I in which Yis methyl, especially those in which the C-atom bonded to a methylresidue Y has the R-configuration.

Furthermore, there are preferred those compounds of formula I in which Zis phenyl or thienyl substituted by carbamoyl, methoxycarbonyl or2-(ethoxy or methoxy)-carbonyl-1-methylvinyl.

Furthermore, there are preferred those compounds of formula I in which Zis p-hydroxyphenyl or phenyl substituted by 6-hydroxyhexoxy,2-ethoxyethoxy, 2-phenethoxy-2-ethoxy or (ethoxy ormethoxy)-carbonylmethoxy.

Especially preferred compounds of formula I are those in which T iscarbomethoxy, X is phenyl monosubstituted by chlorine or trifluoromethylin the meta-position, or phenoxymethyl, Y is methyl and Z isp-hydroxyphenyl or phenyl or thienyl substituted by carbamoyl,methoxycarbonyl or 2-(ethoxy or methoxy)-carbonyl-1-methylvinyl, orphenyl substituted by 6-hydroxyhexoxy, 2-ethoxyethoxy,2-phenethoxy-2-ethoxy or (ethoxy or methoxy)-carbonylmethoxy.

Furthermore, especially preferred compounds of formula I are those inwhich the C-atom bonded to a methyl residue Y has the R-configuration,the C-atom bonded to a phenoxymethyl residue X has the S-configurationand the C-atom bonded to a phenyl residue X has the R configuration.

Examples of preferred compounds of formula I are:

methyl(2RS,5R)-3-[(RS)-4-(5-carbamoyl-2-thienyl)-2-butyl-5-phenyl-2-oxazolidinecarboxylate,

methyl(2RS,5R)-3-[(R)-3-(p-carbamoylphenyl)-1-methylpropyl]-5-phenyl-2-oxazolidinecarboxylateand particularly

methyl(E)-p-[(R)-2-[(2RS,5RS)-2-methoxycarbonyl)-5-(α,α,α-trifluoro-m-tolyl)-3-oxazolidinyl]propyl]-β-methyl-cinnamateand

methyl(2RS,5R)-3-[(R)-3-(p-carbamoylphenyl)-1-methylpropyl]-5-phenoxymethyl-2-oxazolidinecarboxylate.

The oxazolidines of formula I as well as the physiologically compatiblesalts thereof can be used as active substances in pharmaceuticalpreparations for the treatment of obesity and/or diabetes mellitus,especially of obese adult diabetics. In an animal experiment anincreased catabolism, primarily of fat, has been observed upon theadministration of the above compounds. Furthermore, it has been observedthat the compounds stimulate the formation of brown adipose tissue inrats and obese-hyperglycaemic mice. It is known that defects of thebrown adipose tissue play a substantial role in the origin of obesity.In obese-hyperglycaemic mice the compounds have a pronouncedantidiabetic effect, in that they have hypoglycaemic activity and reduceglycosuria. These compounds exhibit only a slight activity on theworking of the heart and circulation. The dosage can amount to 0.5-1000mg, preferably 2-200 mg, per day for an adult depending on the strengthof activity of the individual compounds and on the individualrequirements of the patients, whereby the dosage can be administered asa single dosage or in several dosages divided over the day.

In addition, in an animal experiment with the above compounds anincrease in the body protein content and a decrease in the fat contentcould be detected. These compounds therefore lead to an increase in thelean composition of the body at the expense of fat. Accordingly, theycan be used above all in human medicine for the treatment of conditionswhich are associated with high protein breakdown, e.g. in convalesceneafter an operation. In this case the dosages administered lie in thesame range as in the treatment of obesity and/or of diabetes mellitus.

The above compounds can also be used in the maintenance of fatteninganimals such as beef cattle, pigs, sheep and poultry. In this case thedosages administered and the dosage forms administered can be the sameas in the case of vitamins. These compounds can also be used as feedadditives in dosages of 0.01-100 mg/kg depending on the substance, kindof animal and age.

The pharmaceutical preparations contain the active substance togetherwith a compatible pharmaceutical organic or inorganic carrier materialsuch as e.g. water, gelatine, gum arabic, lactose, starch, magnesiumstearate, talc, vegetable oils, polyalkylene glycols, Vaseline and thelike. The pharmaceutical preparations are preferably administeredorally, e.g. in the form of tablets, capsules, pills, powders,granulates, solutions, syrups, suspensions, elixirs and the like. Theadministration can, however, also be carried out parenterally, e.g. inthe form of sterile solutions, suspensions or emulsions. Thepharmaceutical preparations can be sterilized and/or can containingredients such as preserving agents, stabilizers, wetting agents,emulsifiers, salts for varying the osmotic pressure and buffersubstances.

The activity of the above compounds is evident from the following testresults:

(1) Activity on oxygen consumption

Male albino rats weighing 160-180 g were placed in metabolic cages afterfasting for 24 hours. The cages were ventilated with a constant 6 literroom air/minute which was equilibrated at a dew point of 11° C. Samplesof the spent air were collected during periods of in each case 14minutes after again equilibrating and the oxygen content and CO₂ contentwere analyzed. After an adaptation time of 4 hours the animals, dividedinto groups of 6, received either placebo (5% gum arabic) or the testsubstance (suspended in 5% gum arabic) per os. Thereafter, thedeterminations were carried out for a period of 12 hours. In Table Ithere is given the percentage of the average oxygen consumption aftermedication during the first 3 hours and the entire test duration (12hours) of the oxygen consumption of the adaptation period, correspondingcorrections for variations in the placebo group having been taken intoconsideration.

                  TABLE I                                                         ______________________________________                                        Compound             O.sub.2 consumption of the                               prepared in                                                                              Dosage    of the value of the pre-period                           Example No.                                                                              μ/kg   1st-3rd hour                                                                             1st-12th hour                                 ______________________________________                                        1          1         135        110                                           2          30        148        113                                           3          30        143        113                                           4a         3         133        111                                           4b         10        161        121                                           4c         3         147        133                                           4d         1         131        113                                           4e         10        147        123                                           4f         10        154        117                                           4g         100       137        112                                           4h         30        125        111                                           4i         30        153        121                                           ______________________________________                                    

(2) Catabolic activity on lipids

Groups of 4 male albino rats weighing 320-360 g were kept in metaboliccages without access to feed. Oxygen consumption and CO₂ production weremeasured during 12 hours. After 4 hours the animals received placebo (5%gum arabic) or the test substance (suspended in gum arabic) per os. InTable II there is given the average decrease of the respiratory quotient(CO₂ /O₂) during 8 hours after administration of the test substance incomparison to the last 3 hours before administration of the testsubstance. Variations appearing in the placebo group were taken intoconsideration in the calculation.

                  TABLE II                                                        ______________________________________                                        Compound                                                                      prepared in   Dosage  Variation of the                                        Example No.   μM/kg                                                                              respiratory quotient                                    ______________________________________                                        (4c)          10      -0.035                                                  ______________________________________                                    

(3) Activity on urine glucose and blood glucose and the formation ofbrown adipose tissue

Female hyperglycaemic fat mice were adapted to an amount of feed limitedto 3 g/day/animal. The test compounds (suspended in 5% gum arabic) orplacebo (5% gum arabic) were administered orally twice daily during 15days. Urine was collected for 6 days a week and urine glucose wasdetermined. Blood glucose and the weight of the interscapular brownadipose tissue were determined at the end of the test.

The test results are given in Table III as a percentage of the controlvalue.

                  TABLE III                                                       ______________________________________                                        Compound Dosage                       Brown                                   prepared in                                                                            μM/kg Urine glucose Blood adipose                                 Example No.                                                                            per day  1st week/                                                                              2nd week                                                                             glucose                                                                             tissue                                ______________________________________                                        (4c)     60       11%      0%     24%   217%                                  ______________________________________                                    

The amine starting materials used in the following Examples, especiallythe amines of formula II in which X is phenyl optionally monosubstitutedby fluorine, chlorine, trifluoromethyl or lower-alkoxy and the amines offormula IV, are known or can be prepared in a manner known per se, e.g.as described in European Patent Applications 6735, 21636 and 94595.

For the preparation of the amine starting material of Examples 4(h) amixture of 3.8 g of S-1-methyl-3-(4-amino-carbonylphenyl)propylamine and3.60 g of 2,3-epoxypropyl phenyl ether in 30 ml of ethanol and 20 ml ofacetonitrile was heated under reflux for 8 hours. The reaction solutionwas evaporated in vacuo and the residue was chromatographed on 250 g ofsilica gel. 2.4 g of amorphousp-[(S)-3-[bis-[(RS)-2-hydroxyphenoxypropyl]amino]butyl]benzamide werefirstly eluted with the mixture chloroform/n-propanol/25% NH₃(1000:50:5). With the mixture chloroform/n-propanol/25% NH₃ (100:10:1)there were subsequently eluted 3.5 g of purep-[(S)-3-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]butyl]benzamide, m.p.133°-136° (from acetronitrile), [α]_(D) ²⁰ =-2° (c=0.8 in methanol).ε₂₂₃ =15510, ε₂₃₆ =13820.

The amine starting materials of Examples 4(e) and 4(i) were manufacturedanalogously thereto:

p-[(R)-3-[[(RS)-2-Hydroxy-3-phenoxypropyl]amino]butyl]benzmide, m.p.132°-136° (acetonitrile), [α]_(D) ²⁰ =+2° (c=1.0 in methanol), ε₂₂₂=15250, ε₂₃₆ =13630; and

(RS)-p-[3-[(2-hydroxy-3-phenoxypropyl)amino]propyl]benzamide, m.p.121°-122° (acetone), ε₂₂₂ =15170, ε₂₃₅ =13540.

The following Examples illustrate the invention in more detail.

EXAMPLE 1

1.91 g of5-[(RS)-3-[[(R)-β-hydroxyphenethyl]amino]butyl]-2-thiophenecarboxamideand 0.8 g of methyl glyoxylate were stirred at 25° C. for 5 hours in 60ml of benzene. The reaction mixture was diluted with MeOH and ethylacetate and washed with water, dried over sodium sulphate and evaporatedin vacuo. Chromatography of the residue on silica gel with methylenechloride-ether gave 1 g ofmethyl(2RS,5R)-3-[(RS)-4-(5-carbamoyl-2-thienyl)-2-butyl-5-phenyl-2-oxazolidinecarboxylate,[α]_(D) =-41° (0.1% in dioxan); ε₂₇₇ =10400, ε₂₅₈ =8000.

EXAMPLE 2

1.91 g of methyl5-[3-[[(R)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxylate and1.05 g of methyl glyoxylate were heated to reflux in 20 ml of toluenefor 1 hour on a water separator. The reaction mixture was diluted withethyl acetate and washed with water. The ethyl acetate solutions weredried and evaporated in vacuo. Chromatography of the residue on silicagel gave 1.5 g ofmethyl(2RS,5R)-3-[3-(5-carbomethoxy-2-thienyl)propyl]-5-phenyl-2-oxazolidinecarboxylate,[α]_(D) =-12° (0.1% in dioxan); ε₂₇₈ =12300, ε₂₅₅ =9300.

EXAMPLE 3

In analogy to Example 1 there was preparedmethyl(2RS,5R)-3-[2-(5-carbamoyl-2-thienyl)ethyl]-5-phenyl-2-oxazolidinecarboxylate,[α]_(D) =-12° (c=0.1% in dioxan), ε₂₅₈ =8840, ε₂₇₅ 10660.

EXAMPLE 4

In a manner analogous to Example 2 there were prepared:

(a) Methyl3-[3-(p-carbamoylphenyl)propyl]-5-phenyl-2-oxazolidinecarboxylate, m.p.142°-144° (acetone-hexane), [α]_(D) ²⁰ =+17° (c=0.3 in methanol), ε₂₃₆=14520;

(b)methyl(2RS,5R)-3-[(S)-3-(carbamoylphenyl)-1-methylpropyl]-5-phenyl-2-oxazolidinecarboxylate,amorphous, [α]_(D) ²⁰ =+6° (c=0.4 in methanol), ε₂₃₆ =14150;

(c)methyl(E)-p-[(R)-2-[(2RS,5RS)-2-methoxycarbonyl)-5-(α,α,.alpha.-trifluoro-m-tolyl)-3-oxazolidinyl]propyl]-β-methyl-cinnamate,amorphous, [α]_(D) ²⁰ =-28° (c=0.5 in methanol), ε₂₇₁ =14800;

(d)methyl(2RS,5R)-3-[(R)-3-(p-carbamoylphenyl)-1-methylpropyl]-5-phenyl-2-oxazolidinecarboxylate,amorphous, [α]_(D) ²⁰ =-67° (c=1.0 in methanol), ε₂₃₆ =13600;

(e)methyl(2RS,5R)-3-[(R)-3-(p-carbamoylphenyl)-1-methylpropyl]-5-phenoxymethyl-2-oxazolidinecarboxylate,amorphous, [α]_(D) ²⁰ =-13° (c=0.6 in methanol), ε₂₂₂ =14730, ε₂₃₇=13540;

(f)methyl(2RS,5R)-3-[(S)-p-carbamoyl-α-methylphenethyl]-5-phenyl-2-oxazolidinecarboxylate,amorphous, [α]_(D) ²⁰ =+40° (c=0.4 in methanol), ε₂₃₄ =14000;

(g)methyl(2RS,5R)-3-[(S)-3-(p-hydroxyphenyl)-1-methylpropyl]-5-phenyl-2-oxazolidinecarboxylate,amorphous, [α]_(D) ²⁰ =+11° (c=0.9 in methanol), ε₂₂₄ =11000;

(h)methyl(2RS,5RS)-3-[(S)-3-(p-carbamoylphenyl)-1-methylpropyl]-5-(phenoxymethyl)-2-oxazolidinecarboxylate,amorphous, [α]_(D) ²⁰ =+12° (c=0.5 in methanol), ε₂₂₂ =13640, ε₂₃₈=13000;

(i)methyl(2RS,5RS)-3-[3-(p-carbamoylphenyl)-propyl]-5-phenoxymethyl)-2-oxazolidinecarboxylate,amorphous, ε₂₂₂ =14900, ε₂₃₆ =13550.

EXAMPLE 5

In analogy to Example 1, starting from methyl glyoxylate and(RS)-1-[[3-[5-[(dibutylamino)methyl]-2-thienyl]propyl]amino]-3-phenoxy-2-propanolthere was obtainedmethyl(2RS,5RS)-3-[3-[5-[(dibutylamino)methyl]-2-thienyl]propyl]-5-phenoxymethyl-2-oxazolidinecarboxylate,ε₂₂₀ =12900, ε₂₄₀ =9520, ε₂₇₀ =1930, ε₂₇₇ =1500.

The propanolamine starting material can be prepared as follows:

(a) 2-(p-Toluenesulphonyloxy)-propylthiophene was reacted with acetylchloride and aluminium trichloride in methylene chloride to give5-acetyl-2-(p-toluenesulphonyloxy)-propylthiophene. With sodium azide inDMSO there was obtained therefrom 5-(3-azidopropyl)-2-thienyl methylketone. Oxidation with sodium hypobromite gave5-(3-azidopropyl)-2-thiophenecarboxylic acid, m.p. 71°-72°. Reaction ofthis acid with thionyl chloride and subsequent treatment with conc.ammonia yielded 5-(3-azidopropyl)-2-thiophenecarboxamide, m.p. 85°-87°.There was obtained therefrom after treatment with triphenylphosphine andhydrolysis 5-(3-aminopropyl)-2-thiophenecarboxamide, m.p. 143.5°-144°(from water).

(b) Via 5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide,m.p. 144°-146° C. and by reaction with n-butyl bromide, the product of(a) was butylated to5-(3-aminopropyl-N,N-dibutyl-2-thiophenecarboxamide, ε₂₄₅ =8610, ε₂₇₃=8310.

(c) The product of (b) was reacted with 2,3-epoxypropyl phenyl ether inDMSO at 90° C. to give5-[3-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]propyl]-N,N-dibutyl-2-thiophenecarboxamide,ε₂₁₉ =13150, ε₂₄₄ =9260, ε₂₇₀ =10240, ε₂₇₆ =9960.

(d) The product of (c) was reacted with LiAlH₄ in THF at roomtemperature to give(RS)-1-[[3-[5-[(dibutylamino)methyl]-2-thienyl]propyl]amino]-3-phenoxy-2-propanol,ε₂₂₀ =13050, ε₂₄₀ =9350, ε₂₇₀ =1950, ε₂₇₇ =1560.

EXAMPLE 6

387 mg of(RS)-1-[[(R)-3-[α-(butylamino)-p-tolyl]-1-methylpropyl]amino]-3-phenoxy-2-propanol,102 mg of methyl glyoxylate and 195 mg of p-toluenesulfonic acidmonohydrate in 5 ml of benzene were stirred at 20°-25° C. for 6 hours.The mixture was worked up with ether and sodium bicarbonate solution.Chromatography of the crude product on silica gel with ether-methanolgavemethyl(2RS,5RS)-3-[(R)-3-[α-(butylamino)-p-tolyl]-1-methylpropyl]-5-phenoxymethyl-2-oxazolidinecarboxylate,[α]_(D) =-9° (c=0.1 in methanol); ε₂₁₉ =18140, ε₂₇₀ =1830, ε₂₇₇ =1430.

The propanolamine starting material can be prepared as follows:

(a) Via p-[(R)-3-(2,5-dimethylpyrrol-1-yl)butyl]benzamide,p-[(R)-3-aminobutyl]benzamide was butylated top-[(R)-3-aminobutyl]-N-butylbenzamide, [α]_(D) =+4° (0.1% in methanol).

(b) The product of (a) was reacted at 90° C. with 2,3-epoxypropyl phenylether in DMSO to givep-[(R)-3-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]butyl]-N-butylbenzamide,[α]_(D) =+5° (0.1% in methanol)

(c) 2.1 g ofp-[[(R)-3-[(RS)-2-hydroxy-3-phenoxypropyl]amino]butyl]-N-butylbenzamidein 92 ml of THF were treated portionwise with 920 mg of LiAlH₄ andboiled at reflux for 4 hours. The reaction mixture was decomposed with25 ml of 2N NaOH, diluted with water and extracted three times withmethylene chloride. The methylene chloride solutions were washed withwater, dried and evaporated in vacuo. There were obtained 2.06 g of(RS)-1-[[(R)-3-[α-(butylamino)-p-tolyl]-1-methylpropyl]amino]-3-phenoxy-2-propanol,[α]₃₆₅ -+6° (0.1% in MeOH).

EXAMPLE 7

In analogy to the foregoing Examples, there were prepared:

Methyl(R)-3-[(R)-p-(methoxycarbonyl)-α-methylphenethyl[-5-phenyl-2-oxazolidinecarboxylate,amorph, [α]_(D) ²⁰° =-47° (c=0.25 in MeOH)

methyl(S)-3-[(R)-p-hydroxy-α-methylphenethyl]-5-(phenoxymethyl)-2-oxazolidinecarboxylate,amorph, [α]_(D) ²⁰° =-23° (c=0.2 in MeOH)

methyl(R)-3-[3-[p-(methoxycarbonyl)phenyl]propyl]-5-phenyl-2-oxazolidinecarboxylate,amorph, [α]_(D) ²⁰° =-21° (c=0.3 in MeOH)

methyl(RS)-3-[3-[p-(methoxycarbonyl)phenyl]propyl]-5-(α,α,.alpha.-trifluoro-m-tolyl)-2-oxazolidinecarboxylate,amorph,

methyl(R)-3-[(R)-p-acetyl-α-methylphenethyl]-5-phenyl-2-oxazolidinecarboxylate,amorph, [α]_(D) ²⁰° =-79° (c=0.5 in MeOH)

methyl(R)-3-[(S)-3-[p-(dimethylcarbamoyl)phenyl]-1-methylpropyl]-5-phenyl-2-oxazolidinecarboxylate,amorph, [α]_(D) ²⁰° =-42° (c=0.3 in MeOH).

EXAMPLE 8

Tablets of the following composition are manufactured in the usualmanner:

    ______________________________________                                        Active substance. e.g. methyl (E)--p-[(R)--2-                                 [(2RS,5RS)--2-methoxycarbonyl-5-(trifluoro-m-                                 tolyl)-3-oxazolidinyl]propyl]-β-methyl-cinna-                            mate or                                                                       p-[(S)--3-methyl-3-[(R)--5-phenyl-3-oxazolidi-                                nyl]propyl]benzamide        250 mg                                            Lactose                     200 mg                                            Maize starch                300 mg                                            Maize starch paste          50 mg                                             Calcium stearate            5 mg                                              Dicalcium phosphate         45 mg                                             ______________________________________                                    

We claim:
 1. A method of treating disease conditions characterized by anincreased protein breakdown, which method comprises administering apharmaceutically effective amount of a compound of the formula ##STR10##wherein n is the number 1 or 2,T is lower-carbalkoxy, X is phenoxymethyloptionally mono-fluorinated or mono-chlorinated in the ortho-position orphenyl optionally monosubstituted by fluorine, chlorine, trifluoromethylor lower-alkoxy, Y is hydrogen or methyl, Z is a group of the formula##STR11## R¹ is lower-alkyl, optionally N-mono-lower-alkylated orN-di-lower-alkylated aminomethyl or a residue --C(O)R²,--C(R³)═CH--(CH₂)_(m) --C(O)R², --C(H,R³)--(CH₂)_(m+1) --C(O)R²,--C(H,R³)--(CH₂)_(p) --OH or --C(R³)═CH--C(CH₃)═CH--COOCH₃, R¹¹ ishydroxy, lower-alkoxy, lower-alkanoyloxy, sulphamoyl, benzyloxy orphenoxy or a group R¹, --O--(CH₂)_(q) --OH, --O--(CH₂)_(q) --COOR⁴##STR12## R² is hydroxy, lower-alkyl, lower-alkoxy, dimethylaminoethoxy,lower-alkoxycarbonylethyl or optionally mono-lower-alkylated ordi-lower-alkylated amino, R³ is hydrogen or methyl, R⁴ is lower-alkyl,R⁵ is hydrogen, lower-alkyl or phenyl optionally para-substituted bychlorine, fluorine, trifluoromethyl, lower-alkyl or lower-alkoxy, R⁶ islower-alkyl or phenyl optionally para-substituted by fluorine, chlorine,lower-alkyl or lower-alkoxy, m and p are whole numbers of 0 to 6, v is awhole number of 2 to 4, q and t are whole numbers of 1 to 6, or aphysiologically compatible salt thereof.
 2. A method of treatingdiabetes which method comprises administering an effective amount of acompound of formula ##STR13## wherein n is the number 1 or 2,T islower-carbalkoxy, X is phenoxymethyl optionally mono-fluorinated ormono-chlorinated in the ortho-position or phenyl optionallymonosubstituted by fluorine, chlorine, trifluoromethyl or lower-alkoxy,Y is hydrogen or methyl, Z is a group of the formula ##STR14## R¹ islower-alkyl, optionally N-mono-lower-alkylated or N-di-lower-alkylatedaminomethyl or a residue --C(O)R², --C(R³)═CH--(CH₂)m--C(O)R²,--C(H,R³)--(CH₂)_(m+1) --C(O)R², --C(H,R³)--(CH₂)p--OH or--C(R³)═CH--C(CH₃)═CH--COOCH₃, R¹¹ is hydroxy, lower-alkoxy,lower-alkanoyloxy, sulphamoyl, benzyloxy or phenoxy or a group R¹,--O--(CH₂)_(q) OH, --O--(CH₂)_(q) --COOR⁴ --O--(CH₂)_(q) --O--(CH₂)_(t)--R⁵ or ##STR15## R² is hydroxy, lower-alkyl, lower-alkoxy,dimethylaminoethoxy, lower-alkoxycarbonylethyl or optionallymono-lower-alkylated or di-lower-alkylated amino, R³ is hydrogen ormethyl, R⁴ is lower-alkyl, R⁵ is hydrogen, lower-alkyl or phenyloptionally para-substituted by chlorine, fluorine, trifluoromethyl,lower-alkyl or lower-alkoxy, R⁶ is lower-alkyl or phenyl optionallypara-substituted by fluorine, chlorine, lower-alkyl or lower-alkoxy, mand p are whole numbers of 0 to 6, v is a whole number of 2 to 4, q andt are whole numbers of 1 to 6, or a physiologically compatible saltthereof.
 3. A method of treating obesity which method comprisesadministering an effective amount of a compound of formula ##STR16##wherein n is the number 1 or 2,T is lower-carbalkoxy, X is phenoxymethyloptionally mono-fluorinated or mono-chlorinated in the ortho-position orphenyl optionally monosubstituted by fluorine, chlorine, trifluoromethylor lower-alkoxy, Y is hydrogen or methyl, Z is a group of the formula##STR17## R¹ is lower-alkyl, optionally N-amino-lower-alkylated orN-di-lower-alkylated aminomethyl or a residue --C(O)R²,--C(R³)═CH--(CH₂)m--C(O)R², --C(H,R³)--(CH₂)_(m+1) --C(O)R²,--C(H,R³)--(CH₂)p--OH or --C(R³)═CH--C(CH₃)═CH--COOCH₃, R¹¹ is hydroxy,lower-alkoxy, lower-alkanoyloxy, sulphamoyl, benzyloxy or phenoxy or agroup R¹, --O--(CH₂)_(q) OH, --O--(CH₂)_(q) --COOR⁴ --O--(CH₂)_(q)--O--(CH₂)_(t) --R⁵ or ##STR18## R² is hydroxy, lower-alkoxy,lower-alkoxy, dimethylaminoethoxy, lower-alkoxycarbonylethyl oroptionally mono-lower-alkylated or di-lower-alkylated amino, R³ ishydrogen or methyl, R⁴ is lower-alkyl, R⁵ is hydrogen, lower-alkyl orphenyl optionally para-substituted by chlorine, fluorine,trifluoromethyl, lower-alkyl or lower-alkoxy, R⁶ is lower-alkyl orphenyl optionally para-substituted by fluorine, chlorine, lower-alkyl orlower-alkoxy, m and p are whole numbers of 0 to 6, v is a whole numberof 2 to 4, q and t are whole numbers of 1 to 6, or a physiologicallycompatible salt thereof.
 4. A method in accordance with claim 1 whereinT is carbomethoxy.
 5. A method in accordance with claim 4, wherein thecompound of formula I ismethyl(E)-p-[(R)-2-[(2RS,5RS)-2-methoxycarbonyl)-5-(α,α,.alpha.-trifluoro-m-tolyl-3-oxazolidinyl]propyl]-β-methyl-cinnamate.6. A method in accordance with claim 2 wherein T is carboxymethoxy.
 7. Amethod in accordance with claim 6 wherein the compound of formula I ismethyl(E)-p-[(R)-[(2RS,5RS)-2-methoxycarbonyl)-5-(α,α,α-trifluoro-m-tolyl-3-oxazolidinyl]propyl]-β-methyl-cinnamate.8. A method in accordance with claim 3 wherein T is carbomethoxy.
 9. Amethod in accordance with claim 8, wherein the compound of formula I ismethyl(E)-p-[(R)-[(2RS,5RS)-2-methoxy-carbonyl)-5-(α,α,.alpha.-trifluoro-m-tolyl-3-oxazolidinyl]propyl]-β-methyl-cinnamate.